The incidence of Barrett's esophageal and gastro-esophageal junctional adenocarcinoma is rising faster than that of any other cancer in the United States. Barrett's Esophagus (BE) is a high risk factor for developing these malignancies. Our diagnostic, preventive, and therapeutic approaches to BE and esophageal adenocarcinoma are currently limited. In order to combat this health burden, novel avenues to better understand this lethal cancer's development must be employed. The development of diagnostic and prognostic biomarkers for patients with BE or its sequalae is desperately needed. Our specific aims are: Aim 1: Molecular profiling of Barrett's esophagus and adenocarcinoma, Aim 2: Characterization and validation of molecular targets and Aim 3: Development of diagnostic and prognostic biomarkers for BE progression risk. Global gene expression analyses using serial analysis of gene expression (SAGE) and protein profiling using high resolution 2D gels and mass spectrometry as proposed in this application will characterize the molecular signatures for the development of Barrett's esophagus and incorporate them into a working model of Barrett's tumorigenesis. Our combined mRNA and proteomic analysis approaches will facilitate the discovery of molecular biomarkers such as genes encoding secreted and cell surface proteins. Confirmation of biological and clinical importance in expanded functional and validation testing will be continued. Signature biomarkers once validated as critical in Barrett's adenocarcinoma development have important practical as well as biological implications for improved early diagnostic, prognostic, and therapeutic advances in this lethal disease. Moreover, our analyses will facilitate the discovery of molecular biomarkers such as genes encoding secreted and cell surface proteins providing new opportunities for biomarker assays in the serum.